Exon 53-Skipping Drug from Sarepta Showing Promise

James Radke

Just in time for World Duchenne Awareness Day, Sarepta Therapeutics has announced that golodirsen, the company’s latest drug in development for Duchenne muscular dystrophy (DMD), is showing promise in early clinical studies.

The company presented preliminary results from its Phase 1/2 trial involving DMD patients amenable to exon 53-skipping therapy, stating that all 25 patients in the trial are responding to treatment.

Mutations in the Dystrophin gene lead to low levels of the dystrophin protein and are the primary cause of the progressive degenerative muscle disorder DMD. Without that protein, the muscles slowly die. Symptoms typically begin when a patient is 4-to-5 years old, and affected individuals are commonly non-ambulatory by their teenage years.

Several mutations along the Dystrophin gene can lead to DMD, and Sarepta’s drugs are being developed to ‘skip over’ said mutations, thus allowing the protein to be synthesized. While the first drug to be approved for DMD, Exondys 51 (eteplirsen), is for patients amenable to exon 51 skipping. Golodirsen is for DMD boys amenable to exon 53 skipping.

The Phase 1/2 study is a 2-part study underway in Europe. In Part 1, 12 patients received a dose titration of golodirsen (n=8) or placebo (n=4).  At the end of Part 1 (dose titration), all 12 patients were given golodirsen and an additional 13 patients began golodirsen treatment (Part 2). 

The company announced that after 48 weeks of treatment with golodirsen, all 25 boys in the Part 2 study showed a response to treatment, as measured by dystrophin levels from muscle biopsy samples.

Mean dystrophin protein increased to 1.019% of normal compared to a mean baseline of 0.095% of normal (p < 0.001) as measured by Western blot analysis. While the 1% many not seem like much, that represents a 10.7 fold increase from baseline and does indicate that the drug is increasing synthesis of dystrophin. Whether that is sufficient to halt or slow the progression of the disease is unknown. A recent report by Neri et al (2017) in Neuromuscular Disorders reported that dystrophin levels of 30% or more are needed to avoid DMD. The amount of the protein needed to halt disease progression remains to be determined.

Francesco Muntoni, principal investigator for the study and Pediatric Neurologist, Great Ormond Street Hospital for Children NHS Foundation Trust and the UCL Great Ormond Street Institute of Child Health, said, “These data were also supported by the highly statistically significant increase of dystrophin expression at the sarcolemma, as measured by recently developed validated methodology. This is now the second exon-skipping agent to have shown a statistically significant increase in dystrophin production, validating the exon-skipping approach to treating DMD boys with amenable mutations.”

The study is scheduled to continue for 144 weeks.

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